3 alpha, 7 beta-dihydroxy-5 beta-cholan-24-oic acid ("Ursodeoxycholic acid" or "UDCA") has been used clinically for more than two decades, initially proving effective for the treatment of patients with cholelithiasis and more recently showing promise in the treatment of patients with cholestatic liver diseases. It is well established that oral administration of UDCA leads to a significant improvement in serum liver enzymes, and based on results from long-term clinical trials, the consensus opinion is that UDCA is beneficial for the treatment of early-stage primary biliary cirrhosis. In addition, clinical trials have shown that UDCA is beneficial in improving clinical and biochemical indices of hepatic function in patients with sclerosing cholangitis, cystic fibrosis and chronic hepatitis.
Despite the promising effects shown by UDCA in liver diseases, the exact mechanism of its action remains unclear. Early speculation suggested that a shift in the hydrophobic/hydrophilic balance of the biliary bile acid pool was an important determinant of its effectiveness, but recent data do not totally support this contention; and the improvement in liver function is almost certainly the result of a marked hypercholeresis induced by UDCA, which facilitates the biliary excretion of potentially more toxic bile acids or other endogenous agents.
In studies focussing on the metabolism of UDCA in patients with a variety of liver diseases, the appearance of substantial amounts of the C-3 sulfate ester of UDCA in the urine has been consistently observed, and this specific metabolite has proven to be a useful marker for UDCA compliance. In addition, animal studies have suggested that sulfation of bile acids may represent an important metabolic pathway for preventing cholestasis and limiting hepatocellular damage.
The cytotoxic or membrane-damaging effect of a bile acid is related to its physicochemical properties. Hydrophobic bile acids are markedly more membrane damaging than hydrophilic bile acids, and relative indices of cytotoxicity have been established based on the retention volume of the bile acid in reverse-phase high-pressure liquid chromatography systems or from partition coefficients in octanol/water. It is paradoxical that the human liver synthesizes chenodeoxycholic acid, a hydrophobic molecule that is intrinsically hepatotoxic, as one of its primary bile acids; in cholestasis, the hepatic accumulation of this bile acid may initiate, contribute to, or exacerbate liver damage. In contrast, UDCA, the 7.beta.-epimer of chenodeoxycholic acid, is highly hydrophilic and has been shown to counteract the membrane-damaging effects of hydrophobic bile acids. This is one rationale for the therapeutic use of UDCA in the treatment of a variety of liver diseases. After the oral or intravenous administration of UDCA, this bile acid is efficiently biotransformed in the liver, mainly by conjugation. Negligible concentrations and proportions of unconjugated UDCA are consequently found in human bile, even after the administration of relatively high doses.
UDCA also may have a therapeutic role beyond its use in the treatment of various liver diseases. In this respect, data are emerging from animal models of colonic carcinogenesis that suggest a protective role for UDCA.
However, actual delivery of UDCA to the colon is problematic, in that, at the usual therapeutic doses administered orally (10-15 mg/kg body weight/day), UDCA is relatively well absorbed from the intestine and efficiently biotransformed in the liver mainly by conjugation. As a consequence, it is extremely difficult to deliver effective amounts of UDCA specifically to the colon.
Therefore, given this limitation of delivery to the colon, it would be extremely beneficial to have a compound, composition or method in which UDCA may be effectively delivered to the colon. It also would be desirable to have a compound, composition or method which may be used to deliver UDCA effectively to other portions of the gastrointestinal tract. In addition, it would be advantageous to have a compound, composition or method for use in effectively inhibiting or treating an inflammatory disorder of the gastrointestinal tract or liver.